Induction of Resident Memory CD8+T cell Phenotypes to Eliminate the HIV reservoir

Mancebo Perez, C.; Benitez Rodriguez, A.; Tsukalov, I.; Grau Exposito, J.; Castellvi, J.; Manalich Barrachina, L.; Suanzes, P.; Navarro, J.; Burgos, J.; Curran, A.; Centeno Mediavilla, C.; Falco, V.; Martin Gayo, E.; Buzon, M. J.; Genesca, M.

doi:10.1101/2025.04.09.647906

bioRxiv · 10.1101/2025.04.09.647906

Induction of Resident Memory CD8+T cell Phenotypes to Eliminate the HIV reservoir

Mancebo Perez, C.·Benitez Rodriguez, A.·Tsukalov, I.·Grau Exposito, J.·Castellvi, J.·Manalich Barrachina, L.·Suanzes, P.·Navarro, J.·Burgos, J.·Curran, A.·Centeno Mediavilla, C.·Falco, V.·Martin Gayo, E.·Buzon, M. J.·Genesca, M.

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Abstract

During analytical treatment interruption (ATI), failure to contain tissue HIV reservoirs remains a major barrier to remission. We conditioned peripheral blood mononuclear cells with cues that promote tissue-resident memory differentiation, aiming to reprogram HIV-specific CD8+T cells for these tissue microenvironments. Sequential IL-15/TGF-{beta}1-stimulation expanded proliferative CD103+CD39+ effector populations and restored polyfunctional HIV-specific CD8+T cell responses, irrespective of CD39 or PD-1 expression. Cytokine-stimulated CD8+T cells enhanced ex vivo elimination of the HIV reservoir, and within the induced effector pool, only CD69+ subsets expressing CD103+ or CD39+ eliminated intact HIV-1 genomes. Single-cell transcriptomics showed that IL-15/TGF-{beta}1 stimulation increased clonotypic diversity and expanded resident-like effector clusters with reduced immune-checkpoint receptor expression and augmented mitochondrial function, findings confirmed by flow cytometry. Engrafted recipients from a humanized mouse ATI model more effectively eliminated HIV+-reactivated cells after adoptive transfer of sequentially-treated CD8+T cells. Thus, IL-15/TGF-{beta}1-mediated CD8+T cell reprogramming represents a promising immunotherapy to enable immune control after ATI.

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Mancebo Perez, C., Benitez Rodriguez, A., Tsukalov, I., Grau Exposito, J., Castellvi, J., Manalich Barrachina, L., Suanzes, P., Navarro, J., Burgos, J., Curran, A., Centeno Mediavilla, C., Falco, V., Martin Gayo, E., Buzon, M. J., Genesca, M.. 2025-04-15. Induction of Resident Memory CD8+T cell Phenotypes to Eliminate the HIV reservoir. https://doi.org/10.1101/2025.04.09.647906

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